The present invention is novel compounds which are 2-substituted amino-4,6-di-tertiary-butyl-5-hydroxy-1,3-pyrimidines and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use therefor. The invention compounds have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including, for example, rheumatoid arthritis, osteoarthritis, other inflammatory conditions, pain, fever, psoriasis, allergic diseases, asthma, inflammatory bowel disease, GI ulcers, cardiovascular conditions including ischemic heart disease and atherosclerosis, and ischemia-induced cell damage, particularly brain damage caused by stroke. They can also be used topically for treating acne, sunburn, psoriasis, and eczema. Also included are leukotriene mediated pulmonary, gastrointestinal, inflammatory, dermatological, and cardiovascular conditions. The disclosed compounds also have potential utility as antioxidants. However, overall the preferable use is to treat inflammatory conditions. Thus, the present invention is also a pharmaceutical composition or method of manufacturing a pharmaceutical composition for the use of treating the noted conditions.
2-Substituted-4,6-di-tertiary-butyl-5-hydroxy-1,3-pyrimidines are known to provide activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase as described in co-pending U.S. application Ser. No. PCT/US 92/00443 of Jan. 17, 1992. The compounds described have no amino substituent at the 2-position of the pyrimidine moiety.
Numerous references disclose 2-amino-5-hydroxy pyrimidines. Such disclosed pyrimidines may also be substituted at the 4- and/or 6-positions with various groups including alkyls. For example, U.K. Patent Application Number 2045736 and the Bioch. J. 1951, 48, P. 400 shows the simple 2-amino-5-hydroxy-4,6-dimethylpyrimidine. Other substituted 2-aminopyrimidines are shown in U.S. Pat. No. 4711888, European Publication Numbers 319170, 233416, 1642 and U.S. Pat. Nos. 4,859,679 and 4,940,712.
In summary, the above references do not show the present 2-amino substituent in combination with a 5-hydroxy group and 4 and 6 ditertiarybutyl on a pyrimidine nucleus.